Coronary microvascular obstruction in acute myocardial ... et al.pdfREVIEW Clinical update Coronary microvascular obstruction in acute myocardial infarction Giampaolo Niccoli1*, Giancarla

REVIEW

Clinical update

Coronary microvascular obstruction in acutemyocardial infarctionGiampaolo Niccoli1*, Giancarla Scalone1, Amir Lerman2, and Filippo Crea1

1Institute of Cardiology, Catholic University of the Sacred Heart, Largo F. Vito 1, 00168 Rome, Italy; and 2Division of Cardiovascular Disease, Department of Internal Medicine,Mayo Clinic College of Medicine, Rochester, USA

Received 29 April 2015; revised 23 July 2015; accepted 25 August 2015; online publish-ahead-of-print 12 September 2015

The success of a primary percutaneous intervention (PCI) in the setting of ST elevation myocardial infarction depends on the functional andstructural integrity of coronary microcirculation. Coronary microvascular dysfunction and obstruction (CMVO) occurs in up to half of patientssubmitted to apparently successful primary PCI and is associated to a much worse outcome. The current review summarizes the complexmechanisms responsible for CMVO, including pre-existing coronary microvascular dysfunction, and highlights the current limitations in theassessment of microvascular function. More importantly, at the light of the substantial failure of trials hitherto published on the treatmentof CMVO, this review proposes a novel integrated therapeutic approach, which should overcome the limitations of previous studies.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Microvascular dysfunction † Microvascular obstruction † Acute myocardial infarction

IntroductionST-segment elevation myocardial infarction (STEMI) usually resultsfrom acute thrombotic occlusion of a coronary artery and is a lead-ing cause of death.1 The goal of reperfusion therapy with fibrinolyticdrugs or primary percutaneous coronary intervention (PCI) is to re-store blood flow to ischaemic, but still viable, myocardium, and re-duce infarct size (IS). Accordingly, reducing time to treatment andmaximizing myocardial salvage—in keeping with the mantra that‘time is muscle’—represents a major challenge in the managementof STEMI.2 However, although national door-to-balloon timeshave improved significantly over the last years for patients undergo-ing primary PCI, in-hospital mortality has remained virtually un-changed.3,4 Additional strategies are needed to reduce in-hospitalmortality in this population and attention has to be turned to the de-velopment of systems addressing the continuum of STEMI care,from symptom onset through return to community. To this regard,an unmet need is to address the coronary microvascular functionaland structural obstruction (CMVO), which occurs frequently evenafter prompt epicardial recanalization of the infarct-related artery.Coronary microvascular dysfunction has been shown to increasethe risk of cardiovascular events regardless of the epicardial diseasestatus.5,6 Hence, at the time of reperfusion, patients with pre-existent microvascular dysfunction will benefit less from prompt

reopening of the epicardial vessel, thus underscoring that, preserv-ing a normal microvascular function before acute coronary occlu-sion, is a crucial target of preventive therapies for CMVO similarlyto those aiming at restoring flow in the microcirculation during pri-mary PCI and thereafter in the coronary care unit (CCU). In this art-icle, we review mechanisms, diagnosis, and prognosis of CMVO inacute STEMI, also addressing the prevention and treatment ofCMVO by highlighting the need for an integrated approach in differ-ent time windows.

Mechanisms of coronarymicrovascular dysfunctionand obstruction

Pre-existing coronary microvasculardysfunctionTraditional and non-traditional risk factors play a role in epicardialand microvascular endothelial-dependent dysfunction, specificallyin the high-risk subset with STEMI (Figure 1).5,7 Furthermore, previ-ous studies indicate that abnormal non-endothelium-dependentmicrovascular dilatation appears to be involved in functional andstructural alterations that lead to impaired coronary flow reserve

* Corresponding author. Tel: +39 06 30154187, Fax: +39 06 3055535, Email: [email protected]

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].

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(CFR) with aging, hypertension, diabetes, dyslipidaemia, insulin re-sistance, and chronic inflammatory diseases.7

In one study among patients without obstructive coronary arterydisease (CAD), future cardiovascular events were limited to thosewith a reduction of coronary blood flow in response to intracoron-ary (IC) infusion of acetylcholine.8 Of note, endothelial dysfunctionrepresents an independent predictor of cardiovascular events.9 Ac-cordingly, the presence of angina without evidence of angiographicobstructive CAD is associated with the risk of cardiovascular events,underscoring the potential role of coronary microvascular dysfunc-tion in the pathogenesis of acute coronary syndrome (ACS).10

More specifically, a pre-existing impairment of the myocardialmicrocirculation has been shown to yield greater vulnerability to

PCI-related myocardial injury as well as a poorer long-term out-come.11,12 A pre-existing transient or permanent microvascular dys-function may contribute to the development and prognosis of ACSvia reduction of coronary blood flow, leading to an alteration ofshear stress which aggravates endothelial dysfunction in epicardialarteries and might enhance thrombus formation.5

Ischaemic injuryFour interacting mechanisms cause CMVO in humans: ischaemia-related injury, reperfusion-related injury, distal embolization, and in-dividual susceptibility of the microcirculation to injury (Figure 1).13,14

The first two mechanisms have been translated to humans from theanimal models with a first description by Kloner et al.15 Electron

Figure 1 There are four interacting mechanisms involved in the pathogenesis of coronary microvascular obstruction in humans:ischaemia-related injury, reperfusion-related injury, distal embolization, and individual susceptibility (both genetic and due to pre-existing coornarymicrovascular dysfunction) of the microcirculation to injury. Ischaemic injury: it depends on duration and extent of ischaemia and is characterized bysevere capillary damage, endothelial protrusions, and blebs that block the capillary lumen, and endothelial gaps with extra vascular erythrocytes (inred). Interstitial myocardial oedema compresses capillaries and small arterioles, further decreasing flow through these dysfunctional vessels,whereas sodium and calcium overload explains myocardial cell swelling. Reperfusion injury: the principal determinants of this phenomenon arerepresented by neutrophils (in green), endothelin-1, thomboxane-A2, and platelets (in yellow). The obliteration of vessel lumen by neutrophil-platelet aggregates is associated with release of vasoconstrictors and inflammatory mediators (in brown). Furthermore, in cardiomyocytes, reper-fusion stimulates the production of reactive oxygen species by mitochondria further aggravating microvascular function. Finally, reperfusion mayincrease infarct size due to mitochondria swelling and cell rupture based on opening of the mitochondrial membrane permeability transition, aswell as favour intra-myocardial haemorrhage. Distal embolization: distal embolization (in blue) of plaque and thrombus material may obstruct mech-anically the microcirculation, but it is also a source of vasoconstrictors and procoagulant substances. Both thrombus and plaque features modulatethe effect of distal embolization on coronary microvascular obstruction. Individual susceptibility of the microcirculation to injury: Factors modulatingindividual susceptibility to coronary microvascular obstruction are presented by genetic variability, diabetes, acute hyperglicaemia, hypercholes-terolaemia, and lack of pre-conditioning.

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microscopic analysis after 90 min coronary occlusion followed byreperfusion, revealed severe capillary damage, endothelial protru-sions and blebs that appeared to block the capillary lumen, andendothelial gaps with extra vascular erythrocytes.16 Due to theloss of the glycocalix with expression of P selectin on endothelialcells adhesion of inflammatory cells to the endothelium was com-mon. Furthermore, interstitial myocardial oedema compresses ca-pillaries and small arterioles, further decreasing flow throughthese dysfunctional vessels.15 Sodium and initial calcium overloadexplains myocardial cell swelling, associated to mild opening of mito-chondrial membrane permeability transition pores. Importantly, inthis phase collateral circulation may protect from CMVO.

The most important clinical predictor of ischaemia-related injuryis ischaemia duration, but ischaemic extent also plays an importantrole as confirmed by the association of electrocardiographic, echo-cardiographic, and angiographic indices of myocardial ischaemia ex-tent and prevalence of CMVO.17

Reperfusion injuryWhen ischaemia lasts .3 h, ischaemia-associated injury is poten-tiated by reperfusion injury.18 In particular, lethal reperfusion injury(myocardial necrosis due to reperfusion) and CMVO play a majorrole. Coronary microvascular dysfunction and obstruction is causedby further obliteration of vessel lumen by neutrophil-platelet aggre-gates, which in turn produce large amount of vasoconstrictors andinflammatory mediators.19 Furthermore, in cardiomyocytes, reper-fusion stimulates the production of radical oxygen species by mito-chondria that along with rapid normalization of pH lead to openingof mitochondrial membrane permeability transition pores, calciumoverload, mitochondrial swelling, and cell disruption.19 Again, neu-trophils, a major source of oxidants, proteolytic enzymes, andpro-inflammatory mediators in hearts reperfused in vivo after pro-longed ischaemia, may exacerbate CMVO in humans.19

Moreover, endothelial cells can modulate leucocyte function byexpression of adhesion molecules, e.g. intercellular adhesionmolecule-1 or P-selectin, and by release of soluble factors includingnitric oxide, prostacyclin, and endothelin.17 Finally, functionalchanges during CMVO can be due to release of bioactive factorsfrom coronary plaque (e.g. endothelin-1, tissue factor, and micro-particles) which have the potential to increase the severity of thefunctional impairment of the coronary circulation. Interestingly,one study found that IC infusion of tissue factor in a porcine modelcaused CMVO.20 Moreover, oxidative stress and ischaemia per sereduce the bioavailability of nitric oxide, further contributing tothe dysfunction of the myocardial microcirculation.17

Ischaemia followed by reperfusion may also favour intra-myocardial haemorrhage (IMH). Indeed, hypoxia can disrupt theendothelial barrier and damage the microvasculature and facilitateblood cell extravasation upon reperfusion, thus causing IMH. It isalso possible that activation of inflammation and coagulation leadsto thrombosis, endothelial activation, and therefore consumptionof coagulation factors aggravating the haemorrhage.21

Specific cardiac magnetic resonance (CMR) sequences (T2-weighted and T2*-weighted) identify iron in the tissue, thus showingIMH in up to 40% of patients with CMVO. Of note, in an in vivo por-cine model of reperfused STEMI, IMH at T2-weighted images andat histology showed a close anatomical correlation.22

Importantly, patients with this more severe form of CMVO seemto have a worse outcome than patients with CMVO but withoutIMH.22

Distal embolizationA fourth important mechanism of CMVO is distal embolization.Coronary micro-embolization in experimental models causes re-gional contractile dysfunction due to release of tumour necrosisfactor-alpha. Of note, myocardial perfusion starts falling when mi-crospheres obstruct .50% of coronary capillaries.23 Thus, the smallnumber of emboli during primary PCI in the setting of STEMI, al-though not affecting myocardial perfusion may create a local react-ing milieu with release of inflammatory and vasoactive substancessuch as endothelin-1.23 Moreover, recent evidences demonstratedthat, in patients with STEMI, the coronary neutrophil extracellulartraps (NETs) burden correlates negatively with ST resolution(STR) and positively with IS, thus suggesting that NETs may propa-gate thrombosis and inflammation distally into the infarcted myocar-dium and contribute to myocyte death during atheroembolism.24,25

Similarly, microparticles content of embolized material may worsenreperfusion.26 These observations suggest that embolized materialis biologically active and that may aggravate reperfusion injury be-yond its mechanical obstructive effect on the microcirculation.

Emboli of different size can originate from epicardial coronarythrombus and from fissured atherosclerotic plaques during primaryPCI, but spontaneous embolization has been suspected also beforevessel manipulation. In some cases, an abnormal flow after PCI couldbe due to the dislodgment of an obstructive thrombus distal to theculprit lesion. Of note, this phenomenon is not detectable by angi-ography thus requiring other methods of coronary imaging, like an-gioscopy and optical coherence tomography (OCT).27,28 In thiscontext, as suggested by a recent OCT study, the persistence ofthrombus after stenting may lead to distal embolization even afterstent deployment.29 Interestingly, the effect of angiographically vis-ible distal embolization on IS seems to be time-dependent.30 Bothplaque and thrombus features are associated to risk of distal embol-ization. In particular, thrombus volume is associated with the occur-rence of distal embolization, as well as the presence of a lipid richplaque.31 Furthermore, plaque erosion is more prone to distal em-bolization when compared with plaque rupture in post-mortemstudies, and is more frequently associated to infarctlets, thus sug-gesting that the thrombus type may play an important role. Hence,major predictors of distal embolization are thrombus burden as as-sessed by angiography or IC imaging, and plaque features as assessedby OCT.

Individual susceptibilityA fifth pathogenetic component of CMVO is represented by individ-ual susceptibility to microvascular dysfunction, maybe related to thefunction, as well as to the structure and the density of the microcir-culation.13 Genetic factors may modulate adenosine-induced vaso-dilation. In particular, 1976T.C polymorphism of the adenosine 2Areceptors gene was suspected to be related with a higher preva-lence of CMVO.32 Moreover, genetic variations within defined re-gions of VEGFA and CDKN2B-AS1 genes have been showed tobe associated with coronary microvascular dysfunction, whereassex-specific allelic variants within MYH15, VEGFA, and NT5E genes

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seem to be related with an increased risk of coronary microvasculardysfunction in men.33 Finally, patients with MVCO show a morecompact fibrin network, possibly suggesting a genetic-mediated re-sistance to lysis.34 Another factor modulating the individual suscep-tibility to CMVO is the presence of ischaemic pre-conditioning(IPC), which seems to protect both the myocardium and the coron-ary microcirculation.13 Accordingly, pre-infarction angina might helppreventing CMVO, by inducing IPC. Importantly, beneficial effect ofpre-infarction angina may be blunted in humans due to risk factorsor drugs therapy affecting unfavourably IPC,35 while chronic nitratetherapy seems to stimulate IPC.36

Diagnosis of coronarymicrovascular dysfunctionand obstructionDiagnostic indices may be classified as invasive (Figure 2A) or non-invasive (Figure 2B) tools. Of note, the incidence of CMVO isvariable, ranging from 10% by using angiographic assessment ofthrombolysis in myocardial infarction (TIMI) flow to 60% by usingCMR or myocardial contrast echocardiography (MCE).37 Basedon a combination of angiographic and electrocardiographic indices,a reasonable estimate of patients who get optimal myocardial reper-fusion is �35%.13 Furthermore, due to its dynamic nature, in 50% ofcases CMVO is irreversible, while in the remaining 50% it is revers-ible.38 Of note, the majority of the studies assessing the incidenceof CMVO were performed in patients with STEMI. Indeed, onlyfew studies have assessed CMVO in patients with non-ST-segmentmyocardial infarction (NSTEMI). In particular, these studies includedrather limited numbers of patients and their findings were contro-versial.39,40 Recently, the largest study aimed at detecting the inci-dence of CMVO in a cohort of NSTEMI reported a frequency of13.8%, also establishing the localization of the culprit lesion and aIS as independent predictors of CMVO.41

Invasive indices of coronary microvasculardysfunction and obstructionThe gold standard method for assessing microvascular function isthe direct measurement of coronary blood flow velocity using anIC Doppler wire. In this context, the other tools currently employedto evaluate CMVO, such as ST elevation and biomarkers, may onlyto be considered as surrogate markers. The typical flow pattern as-sociated to CMVO is characterized by: systolic retrograde flow, di-minished systolic anterograde flow, and rapid deceleration ofdiastolic flow. The attenuated CFR response post-PCI is associatedwith future cardiovascular events.42 However, the major obstacleswith this method are the need for special equipment and the useof additional pharmacological interventions.

In this context, compared with CFR, the index of microvascularresistance (IMR) provides a more reproducible assessment ofmicrocirculation, independent of haemodynamic parameters. More-over, it has recently been shown to be a predictor of acute micro-vascular damage and 3-month left ventricular functional recoveryafter primary PCI.43 Again, the hyperaemic microvascular resistance(HMR) index for Doppler-derived coronary flow has been shown tobe associated with ventricular recovery and clinical outcome after

STEMI.44 All together, these insights from clinical pathophysiologycould support therapeutic approaches beyond the primary PCIprocedure itself.

Thrombolysis in myocardial infarction score grading systemdescribes the rate of blood flow in the epicardial vessels, rangingbetween no flow at all (Grade 0) to a normal flow rate (Grade 3);TIMI flow ,3 is a marker of both CMVO and of larger IS and hasbeen shown to affect prognosis both at short and long-term follow-up.45 However, CMVO may occur in nearly 50% of patients withTIMI flow 3. Gibson et al. described the TIMI frame count (TFC) in-dex as the number of frames required for contrast medium to reacha standardized distal landmarks, that may stratify the prognosis of pa-tients exhibiting TIMI flow 3 and correlate with invasive assessmentof CFR.46 In the next years, angiographic methods based on the ki-netics of dye penetration within the myocardium (myocardial‘blush’), the myocardial blush grade (MBG), and TIMI myocardialperfusion grade (TMPG), have been developed in order to shiftthe attention from the epicardial flow to the microcirculatoryflow by angiography.47,48 Myocardial blush grade is a densitometricmethod assessing maximum intensity of contrast medium in themicrocirculation. More intensely, the myocardial blush and fasterits clearance, better the microvascular perfusion. Myocardial blushgrade is scored on a scale of 0–3, with higher scores indicating bet-ter perfusion. The TMPG assesses microvascular clearance of con-trast medium and is scored again on a scale of 0–3. Both MBG andTMPG are able to risk stratify patients having final TIMI flow 3. Thus,it is becoming common practice to define angiographic CMVO, asfollows: TIMI flow grade ,3 or 3 with an MBG or TMPG 0 to1.37 Angiographic methods to assess perfusion (TIMI, TFC, andMBG and TMPG) may have reproducibility concern outside core la-boratory centres, thus invasive assessment of microcirculation dur-ing primary PCI are emerging including IC pressure and flow wiresor their combination to detect the presence of CMVO.37 However,no large studies have compared diagnostic accuracy of angiographicvs. wires obtained indices of CMVO so far.

Non-invasive indices of coronarymicrovascular dysfunction andobstructionAfter primary PCI, incomplete STR has been related to CMVO andworse clinical outcome.49 Different methods have been focused onthe assessment of multiple leads or single leads showing maximumST elevation at baseline.49 Thus, a consensus is still lacking aboutwhich leads to analyse, the optimal timing of electrocardiogram(ECG) analysis, and whether standard ECG or continuous ECGmonitoring is preferable. Assessment of single lead STR showingmaximum ST elevation at baseline seems to be as accurate as thesum STR measurements.50 Of note, residual ST-segment elevationwas found to be an independent marker of CMVO in a recent studyand approximately one-third of patients with TIMI flow Grade 3 andMBG 2–3 do not exhibit STR.51 Angiography and ECG are obtainedat two different times after primary PCI and they may reflect differentaspects of myocardial reperfusion, with angiography looking more atthe coronary microcirculation and ECG more at myocardial cells.13

Myocardial contrast echocardiography utilizes ultrasound to visu-alize contrast microbubbles with a rheology similar to that of red


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blood cells that freely flow within patent microcirculation while lackof intra-myocardial contrast opacification is due to microvascularobstruction that predicts functional recovery after STEMI.52 Myo-cardial contrast echocardiography exhibits several limitations: mod-erate spatial resolution, operator dependency, and incomplete leftventricular coverage with suboptimal visualization of the lateralwall, and semi-quantitative assessment of CMVO.

Cardiac magnetic resonance allows multislice imaging with hightissue contrast and high spatial resolution, enabling accurate quanti-fication and localization of CMVO and IS relative to the entire leftventricle. Cardiac magnetic resonance-defined CMVO correlates

with MCE, angiographic, and invasive indices used for the assess-ment of CMVO.53 In particular, it can be diagnosed as: (i) lack ofgadolinium enhancement during first pass (,2 min) and (ii) lack ofgadolinium enhancement within a necrotic region, identified by lategadolinium hyper-enhancement (after 10–15 min). First pass (early)CMVO is more sensitive than late CMVO, as the latter underesti-mates the extent of CMVO. Cardiac magnetic resonance may giveadditional hints to the presence of IMH that appears to be conse-quence of microvascular injury in humans.21,22 Indeed, a clinicalstudy using CMR imaging for detection of IMH and MCE for detec-tion of perfusion defects, demonstrated that IMH occurred in

Figure 2 The diagnostic indices for coronary microvascular obstruction detection, classified as invasive (green circle) (A) or non-invasive tools(blue circle) (B). Invasive indices: The gold standard method for coronary microvascular dysfunction and obstruction assessment is the directmeasurement of coronary flow reserve using intracoronary Doppler wire; the typical coronary microvascular dysfunction and obstruction patternis characterized by systolic retrograde flow, diminished systolic anterograde flow, and rapid deceleration of diastolic flow. The figure at the bottom,left position, shows the systolic retrograde flow (white arrows) during intracoronary Doppler. The index of microvascular resistance provides amore reproducible assessment of microcirculation, independent of haemodynamic pertubations whereas hyperaemic microvascular resistance isassociated with ventricular recovery and clinical outcome after ST-segment elevation myocardial infarction. The image at the bottom, right pos-ition, shows the typical pattern of coronary microvascular dysfunction and obstruction: reduced coronary flow reserve and increased index ofmicrovascular resistance/hyperaemic microvascular resistance. Angiographic parameters of coronary microvascular dysfunction and obstructionare represented by thrombolysis in myocardial infarction flow score, myocardial blush grade, and thrombolysis in myocardial infarction myocardialperfusion grade. Of note, it is becoming common practice to define angiographic coronary microvascular dysfunction and obstruction as follows:thrombolysis in myocardial infarction flow grade ,3 or 3 with an myocardial blush grade or thrombolysis in myocardial infarction myocardialperfusion grade 0–1. The image at the top shows a case of angiographic coronary microvascular dysfunction and obstruction (white arrow) inthe posterior descending artery of the right coronary artery. Non-invasive indices (light blue circle): ST-segment resolution represents an useful toolof coronary microvascular dysfunction and obstruction, also considering its prognostic value (see the image at the top, left position, for the STbefore opening infarct-related artery; see the image at the top, right position, for the ST after opening infarct-related artery during coronary micro-vascular dysfunction and obstruction). Myocardial contrast echocardiography can be employed for coronary microvascular dysfunction and ob-struction diagnosis. The typical pattern is represented by lack of intra-myocardial contrast opacification (indicated by white arrows, in the image inthe centre, left position). Cardiac magnetic resonance allows multislice imaging with high tissue contrast and high spatial resolution, enabling ac-curate quantification, and localization of coronary microvascular dysfunction and obstruction and infarct size relative to the entire left ventricle;typical signs of coronary microvascular dysfunction and obstruction are represented by lack of gadolinium enhancement during first pass (indicatedby white arrow, in the image at the bottom, on the left position) and lack of gadolinium enhancement within a necrotic region (late gadoliniumhyper-enhancement) (indicated by white arrow, in the image at the bottom, on the right position). Finally, the hybrid positron emission tomog-raphy/cardiac computed tomography allows to monitor inflammatory reactions after reperfusion (indicated by white arrows, within the image inthe centre, on the right position).


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patients with sizable contrast defects only.54 Other imaging tech-niques have been utilized or are under investigation for CMVO de-tection including myocardial scintigraphy or hybrid positronemission tomography-computed tomography, with promising re-sults as they may allow to monitor inflammatory reactions afterreperfusion.55

Prognosis of coronarymicrovascular dysfunctionand obstructionIndices of CMVO predict adverse left ventricular remodelling andmortality after primary PCI (Figure 3; Supplementary material online,Table S1). In particular, TIMI flow ≤2 is associated with an

increased risk of adverse remodelling at 6 months58 and of 5-yearmortality.59 Myocardial blush grade 0–1 increases the risk ofadverse remodelling at 6 months60 and of total mortality after16 months of follow-up.61 Myocardial contrast echocardiographydetected CMVO increases the risk of adverse remodelling at6 months52 and of cardiac death after 46 months.57 Cardiac magneticresonance detected CMVO increases the risk of adverse remodel-ling at 6 months62 and of death.63 The lack of STR increase the risk oftotal mortality after 30 days but failed to consistently predict ad-verse left ventricular remodelling.58 The combination of poorMBG (0 to 1) and lack of STR showed an additive effect on therisk of total mortality after 1 year, thus suggesting that angiographicand ECG indices of CMVO may reflect different pathogenetic me-chanisms.56 Finally, CMR markers of myocardial damage (IS and es-pecially CMVO) provided independent and incremental prognostic

Figure 3 The prognostic role of coronary microvascular obstruction: at the top left, Kaplan–Meier survival curve showing, at long-term follow-up (100 months), that patients in the coronary microvascular obstruction group, evaluated by angiographic thrombolysis in myocardial infarctionflow, had a significantly higher incidence of cardiac death (%), compared with those without coronary microvascular obstruction (log-rankP , 0.0001).45 At the top right, Kaplan–Meier survival curve showing cumulative adverse event rates (%), according to myocardial blush grade,among patients with and without ST-segment resolution, during 1 year follow-up (log-rank P ¼ 0.01). In particular, among patients with ST-seg-ment resolution , 70%, the cumulative adverse event rate was 10.1% for myocardial blush grade 0/1, and 6.3% for myocardial blush grade 2/3.Among patients with ST-segment resolution . 70%, the cumulative event rate was 5.1% for myocardial blush grade 0/1, and 1.2% for myocardialblush grade 2/3.56 At the bottom left, Kaplan–Meier survival curve showing combined event free survival (%) in patients with and without micro-vascular reperfusion, after perfused acute myocardial infarction, evaluated by myocardial contrast echocardiography. In particular, patients with-out microvascular reperfusion exhibit a higher cumulative 5-year combined event rate (long-rank test P , 0.0001), than those withoutmicrovascular dysfunction.57 At the bottom right, Kaplan–Meier survival curve showing combined event free survival (%) in patients with andwithout microvascular obstruction, after perfused acute myocardial infarction, evaluated by magnetic resonance imaging. In particular, patientswith microvascular obstruction exhibit a higher cumulative 2-year combined event rate (long-rank test P ¼ 0.001) than those without microvascu-lar obstruction.22


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information in addition to clinical risk score and left ventricular ejec-tion fraction (LVEF) in a recent large study in patients with STEMI.64

Treatment strategies in differenttime windowsDuring the years, many efforts have been made in order to detect aneffective strategy to prevent and approach CMVO. In this context,management of CMVO should follow the same time windows oftreatment commonly utilized for STEMI patients (Figure 4). Threephases may thus be identified. The first time window is broad andextends until hospital admission for STEMI. The second time win-dow is in catheterization laboratory which provides the unique op-portunity to target directly the coronary microcirculation suppliedby the infarct-related artery. The third time window is, after cath-eterization laboratory, in the coronary care unit where both mech-anical and pharmacological interventions may be implemented toreverse CMVO.

It has to be highlighted that currently no treatment has convin-cingly been proved to be beneficial for the prevention or treatmentof CMVO in a multicenter controlled randomized trial with clinicalendpoints. For this reason, in each time window, we have arbitrarily

divided therapies into three groups: (i) therapies with evidenceand/or general agreement of possible utility and that need to betested in large trials with clinical endpoints, (ii) therapies that stillneed confirmation due to limited or conflicting evidence and/or di-vergence of opinion about their utility (controversial therapies), and(iii) therapies for which the general agreement is that they areineffective (inadequate therapies) (Supplementary material online,Table S2, Figure 4). We hope that this approach might provide a com-prehensive framework for setting up a coordinated therapeuticapproach to the management of CMVO, which spans from preven-tion to treatment.

Before the catheterization laboratoryTherapies to be tested in large trials with clinical endpointsOngoing statin therapy at the time of STEMI was associated to a low-er rate of CMVO, and better functional recovery of myocardial func-tion after 6 months of follow-up when compared with patients noton statin.65 Recently, the administration of high doses of statins priorto primary PCI has been found to improve CMVO when comparedwith that of low doses.66

Regarding b-blockers, pre-clinical studies showed that the third-generation b-blockers like carvedilol and nebivolol are able to

Figure 4 The current treatments of coronary microvascular dysfunction and obstruction in different time windows: before catheterization la-boratory, in the catheterization laboratory, and after catheterization laboratory. In particular, the green circles show the therapies to be tested inlarge trials with clinical endpoints, the green circles report the controversial therapies and the ochre circles show the inadequate treatments. ANP,atrial natriuretic peptide; COX, cyclooxygenase; GIK, glucose–insulin–potassium; IABP, intra-aortic balloon pumping; IC, intracoronary; IPC, is-chaemic post-conditioning; LDD, local drug delivery; RIC, remote ischaemic conditioning; RIPC, remote ischaemic pre-conditioning; rt-PA, recom-binant tissue-type plasminogen activator; SOD, superoxide dismutase.


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protect microcirculation and reduce the IS.67,68 Of note, b-blockersgiven early after chest pain onset may be of utility. Intravenous (IV)metoprolol, administered in ambulance in patients with anteriorSTEMI on Killip class II or less, has been shown to reduce IS, increaseLVEF, and reduce the need for implantable cardioverter-defibrillatorimplantation, with fewer admissions due to heart failure after 2years.69 Among antiplatelet drugs commonly used in STEMI pa-tients, pre-hospital abciximab administration may be useful.70 Ofnote, the FINESSE trial demonstrated that upstream administrationof abciximab with half-dose reteplase significantly reduces IS butdoes not have any overall clinical benefit in primary study endpointat 90 days as well as in mortality at 1 year.71 On the other hand, theOn-TIME-2 trial showed as a routine pre-hospital initiation of high-bolus dose tirofiban might improve STR and clinical outcome afterPCI.72

Conditioning strategies can be implemented after chest pain on-set only. Accordingly, Botker et al. showed that, applying three 5-mincycles of brief ischaemia and reperfusion of the upper arm by usingblood pressure cuff, myocardial salvage was increased in STEMI pa-tients undergoing primary PCI, especially in those with a large area atrisk.73 Of note, adding morphine to remote ischaemic pre-conditioning (RIPC) protocol further improved of STR.74 Thisform of protection is called RIPC, as ischaemia of an organ maylead to protection of a distant organ.

Controversial therapiesResults of studies with the glucose–insulin–potassium (GIK) in thesetting of STEMI have been controversial.75,76 The CREATE ECLAprovided indeed neutral results with no difference in 30 days mor-tality with GIK when compared with placebo.75 Conversely, the re-cent IMMEDIATE trial showed reduction in IS and lower rate ofin-hospital mortality and cardiac arrest in patients randomizedGIK than in controls, with trial treatment started in the ambulanceby paramedics suggesting to start treatments very early after chestpain onset.76 Similarly, the role of chronic treatment and earlyre-administration of ACE inhibitors or nitrates, both associatedwith better reperfusion in small retrospective studies, should betested on a large scale.36,77

Finally, evidence from a new experimental study proposed atherapeutic potential role of NET-targeted intervention in myocar-dial injury-reperfusion injury and CMVO.78 Indeed, DNase I, whichtargets NETs, in combination with recombinant tissue-type plas-minogen activator (rt-PA), which targets fibrin, should be an idealoption to disrupt the NET- and fibrin-provided mesh like backbonestructure of thrombus.

Inadequate therapiesApart from IIb–IIIa inhibitors, new oral antiplatelet drugs have pro-vided conflicting results. In particular, a sub-analysis of PLATO trial,failed to find differences with regard to myocardial perfusion be-tween clopidogrel and ticagrelor79 and in large ATLANTIC study,pre-hospital administration of ticagrelor, in patients with acute STE-MI, did not improve pre-PCI coronary reperfusion as assessed bySTR.80 Of note, among thienopyridines, ticagrelor only was testedin large clinical trials in order to evaluate its effect on pre-PCI cor-onary reperfusion. A small study using CMR to assess CMVOshowed that clopidogrel pre-treatment in STEMI may improve

reperfusion.81 Finally, no data are available regarding the efficacyof prasugrel on CMVO.

ITF-1697, a C-reactive protein-derived tetrapeptide, was tested ina multicentre randomized double-blind study. In particular, IV infu-sion of four dosages of ITF-1697 or placebo was started beforePCI and continued for 24 h. Post-procedure perfusion, assessed byTIMI flow, corrected TFC, MBG, and STR was similar for the placebo.Furthermore, the results showed no differences between the treat-ment regimes in enzymatic IS or clinical outcome up to 30 days.82

On the other hand, starting from previous consistent evi-dences,83,84 a new theoretical basis for the clinical application ofCOX inhibitors in the prevention and treatment of CMVO hasbeen recently provided,85 although their thrombogenic action islikely to be an insurmountable limitation.

Finally, in the CHILL-MI study, hypothermia induced by cold salineand endovascular cooling failed to show a reduction of IS andCMVO.86

In the catheterization laboratoryTherapies to be tested in large trials with clinical endpointsAdenosine can prevent CMVO through several mechanisms. TheAMISTAD trial suggested that IV adenosine started before reperfu-sion might improve the outcome when given early (,3.2 h fromchest pain onset) when compared with placebo.87,88 In the lastfew years, other reports have provided mixed results regardingthe role of IC adenosine.89–93 Differences in way of administration,timing and dosages may explain these discrepancies. In theREOPEN-AMI trial, we found high dosages of IC adenosine, givenafter thrombus aspiration through the aspiration catheter, improvedSTR, and enzymatic IS when compared with placebo or sodium ni-troprusside, which translated in a reduction of major adverse car-diac events (MACEs) and a better left ventricular remodelling at1-year follow-up.94,95

Atrial natriuretic peptide (ANP), cyclosporine, and exenatide,known to have cardioprotective effects, have shown beneficial ef-fects on IS while the effect on indices of CMVO is neutral or not re-ported.96– 98

In the J-Wind trial, ANP, which activates the RISK cardioprotec-tive pathways, reduced enzymatic IS, and improved LVEF.96

Exenatide, a glucagon-like peptide-1 agonist, has been shown toreduce IS when administered at time of reperfusion in animal mod-els. Exenatide, started 15 min before primary PCI and given intra-venously for 6 h post-procedure, increased salvage index but30-day clinical events were similar when compared with placebo.98

Cardioprotection by mechanical remote conditioning may begiven during primary PCI. Indeed, a recent study showed that remoteconditioning (3 cycles of ischaemia/reperfusion of the lower limb) atthe time of primary PCI reduced enzymatic IS, and was associatedwith an improvement of T2-weighted oedema volume assessed byCMR and STR when compared with conventional primary PCI.99

Controversial therapiesInitial small single centre studies about thrombus aspiration showedpromising results with regard to functional or structural indices ofCMVO,100 whereas clinical efficacy was then confirmed in the largerTAPAS101; indeed, at 1-year follow-up mortality was lower in pa-tients randomized to manual thrombus aspiration than in those


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randomized to conventional primary PCI.102 Later, the TASTE trialrandomized 7244 patients with STEMI to manual thrombus aspir-ation or to conventional primary PCI. Death from any cause after30 days occurred in 2.8% and in 3.0% of patients, respectively.103

After 1 year, no mortality benefit was associated with manualthrombus aspiration.104 Eventually, the TOTAL trial has recentlyclarified as, in patients with STEMI undergoing primary PCI, routinemanual thrombectomy when compared with PCI alone did not re-duce the risk of cardiovascular death, recurrent MI, cardiogenicshock, or NYHA class IV heart failure within 180 days but was asso-ciated with an increased rate of stroke within 30 days.105 On theother hand, the Angiojet mechanical thrombectomy device in theJETSTENT study, that included patients with acute MI and angio-graphic evidence of large thrombus burden, showed improvementin STR in the treatment group. Importantly, after 1 year, MACEsrate were 14.9% in the Angiojet group vs. 22.7% in the direct stent-ing group.106 Nevertheless, thrombus aspiration may have some lim-itations. In particular, one recent OCT study failed to show largerlumen area after thrombus aspiration when compared with thatobserved after conventional primary PCI.29 Thus, other approachesincluding stent with trapping capabilities107 and local delivery of ab-ciximab at culprit lesion level through special porous balloon108

failed to improve clinical outcome. Interestingly, in recent a study,patients with STEMI and at least 1 risk factors for CMVO were ran-domized to a strategy of immediate stenting vs. delayed stenting (thevessel was initially recanalized by thrombus aspiration or minimalballoon dilatation followed by IIb– IIIa infusion).109 The authorsshowed lower rate of CMVO and greater myocardial salvage indexat 6 months in the deferred group, thus suggesting that leaving timeform residual thrombus dissolution before stenting may play animportant role in the prevention of CMVO.

Vasodilators may be given in the catheterization laboratory, includ-ing verapamil, diltiazem, and nitroprusside.110,111 While all have beenassociated with improvement of flow by angiography, clinical out-come data are lacking for calcium-antagonists,110 or controversialfor nitroprusside.111

Inadequate therapiesIntracoronary administration of abciximab failed to improve MACEs(all-cause mortality, recurrent MI, and new heart failure) and CMVOrate at 3 months when compared with its IV administration.112 Simi-larly, nicorandil, a hybrid drug of ATP-sensitive K-channel openerand nicotinamide nitrate, in the large J-WIND trial failed to improveclinical outcome.96

While RIPC given early before reperfusion is a promising therapy,post-conditioning that refers to stuttering or interrupted reperfu-sion with a series of brief coronary artery re-occlusion-reperfusioncycles before full and final reperfusion, had disappointing re-sults.113,114 Most but not all studies on post-conditioning haveshown a beneficial effect on IS and CMVO.113 However, the largeststudy so far published which randomized 700 patients to post-conditioning vs.. conventional primary PCI failed to show improve-ment of STR and clinical outcome at 30 days follow-up.114 Anappropriately sized study on post-conditioning with clinicalendpoints and 3 years of follow-up is ongoing (DANAMI-3).

Opening of mitochondrial permeability transition pores has acentral role in reperfusion injury, leading to mitochondria swelling

and cell death. Thus, new area of investigation is focus on protectingthe mitochondria during STEMI. Of note, IV infusion of TRO40303,an inhibitor of the mitochondrial permeability transition pores,failed to reduce IS or improve LVEF in patients with STEMI rando-mized vs. placebo in the MITOCARE study.115

The recent data emerged from EMBRACE study showed as Bend-avia, another potential mitochondria-targeted peptide able to crosscell membranes and reduce ischaemia-reperfusion injury in animalmodels, did not reduce myocardial damage in STEMI patients.116

Drugs able to reduce lethal reperfusion injury have shown nega-tive results. In particular, the APEX-AMI aimed at assessing the effi-cacy of pexelizumab, a humanized monoclonal antibody that bindsthe C5 component of complement, failed to improved 30-days mor-tality as well as TIMI-3 flow rate when compared with placebo.117

On the other hand, the FIRE trial conducted to test the FX06, a pep-tide derived from human fibrin, failed to reduce IS or CMVO as as-sessed by CMR.118 Of note, FX06 is able to compete with E1fragments of fibrin for binding to an endothelial specific molecule,VEcadherin, thereby acting as an anti-inflammatory.

Finally, most of the studies on erythropoietin have shown no ef-fect on IS,119 and supersaturated oxygen therapy showed contro-versial results.120

After the catheterization laboratoryTherapies to be tested in large trials with clinical endpointsThe aggressive risk factors modifications, guidelines-based therapy,and rehabilitation all were proven to have a significant impact on therecurrence of ACS and re-hospitalization. This therapeutic ap-proach may exert its effect at least in part by improving coronarymicrovascular dysfunction. Furthermore, as shown above, somedrug infusions started in the catheterization laboratory may be con-tinued in CCU. In particular, beneficial effects have been shown forIV IIb– IIIa inhibitors,121 adenosine,88 ANP,96 and more recently ex-enatide.98 The duration of IV infusion for such therapies in CCUshould be matter of future studies, as currently tested drugs havebeen given for variable times from 3 to 12 h. More prolonged ther-apies (up to 24 h) may possibly increase the rate of reversibleCMVO that has been described to occur spontaneously in nearlyhalf of patients after 1 month.122

Controversial therapiesThe effect of stem cells on CMVO has provided mixed results.123–125

Indeed, improvement of CFR after cell therapy has not consistentlybeen shown in all trials,123 conversely in the presence of CMVO, theimprovement of LVEF associated to stem cell treatment seems tobe blunted.124 Finally, in a recent study, the addition of cilostazol(for 1 month) to double antiplatelet therapy with aspirin and clopi-dogrel in patients with angiographic CMVO improved the clinicaloutcome after 1 year.126

The use of vasodilators (calcium-channel antagonist, dypirida-mole) or metabolic drugs (ranolazine) at discharge needs futureresearch having as endpoint reversion of CMVO, improved remod-elling, and clinical outcome.127,128 Finally, endothelin-1 may be an-other promising therapeutic target of.129,130


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Inadequate therapiesIntra-aortic balloon pumping (IABP) is able to reduce myocardialoxygen demand due to systolic left ventricular unloading andincreases myocardial perfusion.131,132 However, Maekawa et al.failed to show an increase of mean diastolic flow velocity andpeak diastolic flow velocity in left anterior descending by IABP inpatients with angiographic CMVO.131 Moreover, IABP failed toreduce IS in high-risk PCI.132

ConclusionsThe role of the microcirculation in determining short- and long-term outcome following ACS continues to emerge. In this context,over the past decades many studies have focused on the potentialmechanisms by which reperfusion damage contributes to the micro-vascular abnormalities. The current review highlights a novel aspectsof the complex role of coronary microcirculation in ACS and pro-motes the notion that pre-existing coronary microvascular dysfunc-tion may play a major role in determining CMVO and outcome ofreperfusion strategies following primary PCI. Future trials shouldexplore the effects of integrated treatments aimed at preventionand treatment of coronary microvascular dysfunction in this setting.

Supplementary materialSupplementary material is available at European Heart Journal online.

Authors’ contributionsA.L., F.C.: handled funding and supervision. G.N., G.S., A.L., F.C.: con-ceived and designed the research. G.N., G.S.: drafted the manu-script. A.L., F.C.: Made critical revision of the manuscript for keyintellectual content. G.S., G.N.: the names of the authors who didanything else on the manuscript other than what we have listed.

Conflict of interest: none declared.

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